ApoVax-SVN as a Novel Vaccine for Cancer Immunotherapy

ApoVax-SVN 作为癌症免疫治疗的新型疫苗

• 批准号: 7326239
• 负责人: Haval Shirwan
• 金额: $ 32.83万
• 依托单位: APOVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-06 至 2009-03-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326239
• 关键词: Activated Lymphocyte; Acute; Adjuvant; Adverse effects; Animal Model; Animals; Antibody Formation; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Applications Grants; B-Cell Lymphomas; Binding; Biotin; CD8B1 gene; Cancer Model; Cancer Patient; Cancer Vaccines; Cause of Death; Cell Differentiation process; Cell membrane; Cells; Chimeric Proteins; Clinical; Clinical Trials; Complex; Condition; Dendritic Cells; Dendritic cell activation; Developed Countries; Developing Countries; Development; Disease; Dose; Effectiveness; Enzyme-Linked Immunosorbent Assay; Extracellular Domain; Figs - dietary; Generations; Goals; Grant; Human; Immune; Immune Targeting; Immune response; Immune system; Immunization; Immunologic Memory; Immunotherapy; In Vitro; Inbred BALB C Mice; Injection of therapeutic agent; Life; Ligands; Lymphocyte antigen; Maintenance; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Marketing; Mediating; Modality; Modeling; Modification; Molecular; Mus; Natural Killer Cells; Nature; Operative Surgical Procedures; Patients; Peptides; Phase; Phase I Clinical Trials; Play; Pre-Clinical Model; Prevention; Protein Isoforms; Radiation; Radiation therapy; Recurrence; Research Personnel; Role; Series; Signal Transduction; Small Business Technology Transfer Research; Solutions; Specificity; Staining method; Stains; Streptavidin; Structure; Surface; Survivin Antigen; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Therapeutic; Therapeutic Effect; Treatment Efficacy; Treatment Protocols; Tumor Antigens; United States; Upper arm; Vaccinated; Vaccines; Week; Work; base; cancer cell; cancer immunotherapy; cancer prevention; cancer therapy; cell mediated immune response; chemotherapy; concept; crosslink; cytokine; day; design; desire; in vivo; innovation; interest; macrophage; mouse model; neoplastic; new technology; novel; novel vaccines; prevent; prophylactic; protein function; receptor; response; size; success; survivin; synthetic peptide; therapeutic effectiveness; therapeutic vaccine; tumor; tumor growth; tumor progression; vaccine efficacy

DESCRIPTION (provided by applicant): The main objective of this proposal is to develop a novel cancer vaccine, ApoVax-SVN(tm) based on the use of a proprietary costimulatory chimeric ligand, 4-1BBL, designed to specifically deliver survivin, a tumor associated antigen (TAA) to professional antigen-presenting cells (APCs) and activate them for the generation of an effective anti-tumor immune response with therapeutic efficacy for cancer immunotherapy. Therapeutic vaccines represent an attractive treatment modality for the management of cancer, primarily due to their specificity and ability to induce long lasting immunological memory that may prevent against recurrences. However, their therapeutic potential remains to be realized partially due to the complex nature of interactions taking place between the immune system and cancer cells in the course of tumor progression. These interactions are primarily regulated by two opposing forces; immune mechanisms that target the tumor for destruction and tumor-mediated counter-mechanisms that enable the tumor to evade the immune system. As such, to be effective tumor vaccines must be capable of generating a potent anti-tumor immune response as well as overcoming immune evasive mechanisms for a therapeutic effect. Various cancer vaccine approaches based on the use of TAAs have been developed and shown effective in preclinical models. However, the therapeutic efficacy of these vaccines has been limited in clinical trial settings. Although the reasons for their clinical inefficacy remain unknown, the lack of a strong adjuvant effect, ineffective delivery of TAAs to professional APCs, and/or the presence of significant immunoinhibitory immune evasion mechanisms may contribute to this effect. To overcome some of these difficulties, a novel technology designated as ProtEx(tm) has recently been developed by the Principle Investigator of this application. ProtEx(tm) involves the generation of chimeric immunological ligands with a modified form of core streptavidin, modification of the cell membrane with biotin, and decoration with chimeric proteins. There are three distinct advantages to this technology. First, chimeric ligands exist as tetramers and higher structures, and as such effectively crosslink their receptors on immune cells for potent signal transduction. Second, chimeric proteins can be displayed singly or in a combination on the surface of any biotinylated cell at desired levels in a rapid (< 2 hrs), efficient (100% of the targeted cells), and durable (t1/2= days to weeks) manner without compromising the function of the protein or the cell. Third, chimeric proteins can be conjugated to biotinylated molecules of interest via streptavidin/biotin interaction and used as vehicles to deliver such molecules to cells of interest expressing receptors for the chimeric proteins. The Principle Investigator of this application recently developed a novel, proprietary potential cancer vaccine approach based on the use of 4-1BBL chimeric molecule conjugated to biotinylated TAA antigens. In preliminary studies, this novel vaccine showed potent stimulatory activity on the innate as well as adaptive arms of the immune system and inhibitory activity on T regulatory cells implicated in tumor growth. More importantly, since the last submission of this grant we have demonstrated that immunization with SA-4-1BBL plus a synthetic peptide representing the CD8+ T cell epitope of E7 was effective in eradicating established tumors in a cervical cancer animal model. Therefore, the objectives of this proposal are to test and determine in vivo conditions required for protective as well as therapeutic effects of ApoVax-SVN(tm) vaccine using a B cell lymphoma transplantable model expressing survivin as a TAA. Proof-of-principle confirmation in experimental cancer models will pave the way for testing this novel concept in human clinical trials. Immune system-based treatment of cancer represents an alternative therapeutic approach to classic chemotherapy and radiation treatment, and promises to yield a more definitive solution based on a true molecular approach to cancer. ApoImmune's novel immune system-based therapy, ApoVax104 vaccine, is a new, innovative approach to treating cancer and malignant neoplastic diseases.

描述（申请人提供）：该提案的主要目的是开发一种新型癌症疫苗ApoVax-SVN（tm），其基于使用专有的共刺激嵌合配体4-1BBL，其被设计为特异性递送存活素，肿瘤相关抗原（TAA）专业抗原呈递细胞（APC），并激活它们产生有效的抗肿瘤抗体。肿瘤免疫应答与癌症免疫治疗的治疗功效。治疗性疫苗代表了用于癌症管理的有吸引力的治疗模式，主要是由于它们的特异性和诱导可防止复发的持久免疫记忆的能力。然而，它们的治疗潜力仍有待实现，部分原因是在肿瘤进展过程中免疫系统和癌细胞之间发生相互作用的复杂性。这些相互作用主要由两种相反的力量调节：靶向肿瘤进行破坏的免疫机制和使肿瘤能够逃避免疫系统的肿瘤介导的反机制。因此，有效的肿瘤疫苗必须能够产生有效的抗肿瘤免疫应答以及克服免疫逃避机制以获得治疗效果。已经开发了基于使用TAA的各种癌症疫苗方法，并在临床前模型中显示出有效性。然而，这些疫苗的治疗效果在临床试验环境中受到限制。尽管其临床无效的原因仍然未知，但缺乏强佐剂作用、TAA向专职APC的无效递送和/或存在显著的免疫抑制性免疫逃避机制可能导致这种作用。为了克服这些困难中的一些，本申请的主要研究者最近开发了一种称为ProtEx（TM）的新技术。ProtEx（TM）涉及用核心链霉抗生物素蛋白的修饰形式生成嵌合免疫配体、用生物素修饰细胞膜以及用嵌合蛋白修饰。这项技术有三个明显的优势。首先，嵌合配体作为四聚体和更高结构存在，并且因此有效地交联它们在免疫细胞上的受体以用于有效的信号转导。第二，嵌合蛋白可以以快速（< 2小时）、有效（100%的靶细胞）和持久（t1/2=天至数周）的方式以所需水平单独或组合地展示在任何生物素化细胞的表面上，而不损害蛋白或细胞的功能。第三，嵌合蛋白可以通过链霉亲和素/生物素相互作用与生物素化的目标分子缀合，并用作载体将此类分子递送至表达嵌合蛋白受体的目标细胞。本申请的主要研究者最近开发了一种新的、专有的潜在癌症疫苗方法，该方法基于使用与生物素化TAA抗原缀合的4-1BBL嵌合分子。在初步研究中，这种新型疫苗对免疫系统的先天性和适应性臂显示出有效的刺激活性，并对与肿瘤生长有关的T调节细胞显示出抑制活性。更重要的是，自从上次提交该资助以来，我们已经证明，用SA-4-1BBL加上代表E7的CD 8 + T细胞表位的合成肽进行免疫接种，可有效根除宫颈癌动物模型中已建立的肿瘤。因此，本提案的目的是使用表达存活素作为TAA的B细胞淋巴瘤可移植模型，测试和确定ApoVax-SVN（tm）疫苗的保护性和治疗性效果所需的体内条件。在实验癌症模型中的原理验证将为在人体临床试验中测试这一新概念铺平道路。基于免疫系统的癌症治疗代表了经典化疗和放疗的替代治疗方法，并有望基于真正的癌症分子方法产生更明确的解决方案。ApoImmune的新型免疫系统疗法ApoVax 104疫苗是治疗癌症和恶性肿瘤疾病的一种新的创新方法。

项目成果

SA-4-1BBL costimulation inhibits conversion of conventional CD4+ T cells into CD4+ FoxP3+ T regulatory cells by production of IFN-γ.

• DOI: 10.1371/journal.pone.0042459
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Madireddi S;Schabowsky RH;Srivastava AK;Sharma RK;Yolcu ES;Shirwan H
• 通讯作者: Shirwan H

SA-4-1BBL and monophosphoryl lipid A constitute an efficacious combination adjuvant for cancer vaccines.

• DOI: 10.1158/0008-5472.can-14-1768-a
• 发表时间: 2014-11-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Srivastava AK;Dinc G;Sharma RK;Yolcu ES;Zhao H;Shirwan H
• 通讯作者: Shirwan H

SA-4-1BBL as the immunomodulatory component of a HPV-16 E7 protein based vaccine shows robust therapeutic efficacy in a mouse cervical cancer model.

• DOI: 10.1016/j.vaccine.2010.06.073
• 发表时间: 2010-08-16
• 期刊: VACCINE
• 影响因子: 5.5
• 作者: Sharma, Rajesh K.;Srivastava, Abhishek K.;Yolcu, Esma S.;MacLeod, Kathryn J.;Schabowsky, Rich-Henry;Madireddi, Shravan;Shirwan, Haval
• 通讯作者: Shirwan, Haval